4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs

ABSTRACT

The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs, compositions containing them, and methods of using them as PPAR modulators to treat or inhibit the progression of, for example, dyslipidemia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a continuation application of U.S. application Ser.No. 12/144,061, filed Jun. 23, 2008 now U.S. Pat. No. 7,598,416, whichis a continuation application of U.S. application Ser. No. 11/226,645,now U.S. Pat. No. 7,425,649, filed Sep. 14, 2005, which claims priorityto U.S. Provisional Patent Application No. 60/609,967, filed Sep. 15,2004, the disclosures of which are hereby incorporated by reference intheir entireties.

FIELD OF THE INVENTION

The invention features 4-((phenoxyalkyl)thio)-phenoxyacetic acids andanalogs, compositions containing them, and methods of using them.

BACKGROUND

The peroxisome proliferator-activated receptors (PPARs) are metabolicsensors regulating the expression of genes involved in glucose and lipidhomeostasis. Agonists of the PPARα subtype, such as LOPID® (gemfibrozil)and TRICOR® (fenofibrate), and agonists of the PPARγ subtype, such asAVANDIA® (rosiglitazone maleate), are used for the treatment ofdyslipidemia and diabetes, respectively. Another member of this nuclearreceptor family, the peroxisome proliferator-activated receptor delta(PPAR delta or PPARδ) is also a necessary transcription factor reportedto be involved in regulating genes involved in lipid metabolism andenergy expenditure. PPAR delta has been shown to act as a “gateway”receptor modulating the expression of the other PPARs (Shi et al., 2002,Proc Natl. Acad. Sci. USA, 99(5): 2613-2618). Each receptor subtype hasa distinct tissue distribution: 1) PPARα shows the highest expression inliver, 2) PPARγ appears primarily in adipose tissue, and 3) PPARδ hasthe widest distribution—ubiquitously in adult rat (Braissant et al.,1996, Endocrinology 137(1): 354-366) and in all the human tissues testedto date, including liver, kidney, abdominal adipose and skeletal muscle(Auboeuf et al., 1997, Diabetes 46(8):1319-1327).

The peroxisome proliferator-activated receptor alpha (PPAR alpha orPPARα) is a necessary transcription factor regulating genes relating tofatty acid metabolism and insulin action. The genes regulated by PPARalpha include enzymes involved in the beta-oxidation of fatty acids, theliver fatty acid transport protein, and apo A1, an important componentof high density lipoproteins (HDL). Selective, high affinity PPAR alphaagonists increase hepatic fatty acid oxidation, which in turn decreasescirculating triglycerides and free fatty acids.

Examples of known PPAR alpha agonists variously useful forhyperlipidemia, diabetes, or atherosclerosis include fibrates such asfenofibrate (Fournier), gemfibrozil (Parke-Davis/Pfizer, Mylan, Watson),clofibrate (Wyeth-Ayerst, Novopharm), bezafibrate, and ciprofibrate andureidofibrates such as GW 7647, GW 9578, and GW 9820 (GlaxoSmithKline).

Diabetes is a disease caused, or contributed to, by multiple factors andcharacterized by hyperglycemia which may be associated with increasedand premature mortality due to an increased risk for microvascular andmacrovascular diseases such as nephropathy, neuropathy, retinopathy,atherosclerosis, polycystic ovary syndrome (PCOS), hypertension,ischemia, stroke, and heart disease. Type I diabetes (IDDM) results fromgenetic deficiency of insulin, the hormone regulating glucosemetabolism. Type II diabetes is known as non-insulin dependent diabetesmellitus (NIDDM), and is due to a profound resistance to insulinregulatory effect on glucose and lipid metabolism in the maininsulin-sensitive tissues, i.e., muscle, liver and adipose tissue. Thisinsulin resistance or reduced insulin sensitivity results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue as well as glucose production and secretion in liver. Many TypeII diabetics are also obese, and obesity is believed to cause and/orexacerbate many health and social problems such as coronary heartdisease, stroke, obstructive sleep apnoea, gout, hyperlipidemia,osteoarthritis, reduced fertility, and impaired psychosocial function.

A class of compounds, thiazolidinediones (glitazones), have beensuggested to be capable of ameliorating many symptoms of NIDDM bybinding to the peroxisome proliferator activated receptor (PPAR) familyof receptors. They increase insulin sensitivity in muscle, liver andadipose tissue in several animal models of NIDDM resulting in correctionof the elevated plasma levels of glucose, triglycerides andnonesterified free fatty acids without any occurrence of hypoglycemia.However, undesirable effects have occurred in animal and/or humanstudies including cardiac hypertrophy, hemadilution and liver toxicity.

Many PPARγ agonists currently in development have a thiazolidinedionering as a common structural element. PPARγ agonists have beendemonstrated to be extremely useful for the treatment of NIDDM and otherdisorders involving insulin resistance. Troglitazone, rosiglitazone, andpioglitazone have been approved for treatment of Type II diabetes in theUnited States. There is also some indication thatbenzimidazole-containing thiazolidinedione derivatives may be used totreat irritable bowel disorder (IBD), inflammation, and cataracts (JP10195057).

Cardiovascular disease (CVD) is prevalent in the world and is oftenassociated with other disease states such as diabetes and obesity. Manypopulation studies have attempted to identify the risk factors for CVD;of these, high plasma levels of low density lipoprotein cholesterol(LDL-C), high plasma levels of triglycerides (>200 mg/dl), and lowlevels of high density lipoprotein cholesterol (HDL-C) are considered tobe among the most important. Currently, there are few therapiestargeting low HDL-C and triglycerides.

Recently, potent ligands for PPARδ have been published, providing abetter understanding of its function in lipid metabolism. The maineffect of these compounds in db/db mice (Leibowitz et al., 2000, FEBSLett. 473(3):333-336) and obese rhesus monkeys (Oliver et al., 2001,Proc. Natl. Acad. Sci. USA 98(9):5306-5311) was an increase in highdensity lipoprotein cholesterol (HDL-C) and a decrease in triglycerides,with little effect on glucose (although insulin levels were decreased inmonkeys). HDL-C removes cholesterol from peripheral cells through aprocess called reverse cholesterol transport. The first andrate-limiting step, a transfer of cellular cholesterol and phospholipidsto the apolipoprotein A-I component of HDL, is mediated by the ATPbinding cassette transporter A1 (ABCA1) (Lawn et al., 1999, J. Clin.Investigation 104(8): R25-R31). PPARδ activation has been shown toincrease HDL-C level through transcriptional regulation of ABCA1 (Oliveret al., 2001, Proc. Natl. Acad. Sci. USA 98(9): 5306-5311). Throughinduction of ABCA1 mRNA expression in macrophages, PPARδ agonists mayincrease HDL-C levels in patients and remove excess cholesterol fromlipid-laden macrophages, thereby inhibiting the development ofatherosclerotic lesions. Existing therapy for hypercholesterolemiaincludes the statin drugs, which decrease LDL-C but show little effecton HDL-C, and the fibrates, the PPARα agonists that have low potency andinduce only modest HDL-C elevation. In addition, like the fibrates,PPARδ agonists may also reduce triglycerides, an additional risk factorfor cardiovascular disease and diabetes. Elevated free fatty acid levelhas been shown to contribute to insulin resistance and progression ofdiabetes (Boden, G. PROCEEDINGS OF THE ASSOCIATION OF AMERICANPHYSICIANS (1999 May-June), 111(3), 241-8).

Examples of known PPAR delta agonists variously useful forhyperlipidemia, diabetes, or atherosclerosis include L-165041 (Leibowitzet al., 2000) and GW501516 (Oliver et al., Proceedings of the NationalAcademy of Sciences of the United States of America (2001), 98(9),5306-5311). Treatment of differentiated THP-1 monocytes with GW501516induced ABCA1 mRNA expression and enhanced cholesterol efflux from thesecells.

SUMMARY OF THE INVENTION

The invention features compounds of Formula (I) below:

wherein

-   -   X is selected from a covalent bond, S, and O;    -   Y is S or O;    -   Z is O or CH₂, provided when Y is O then Z is O;    -   R₁ and R₂ are independently selected from H, C₁₋₃ alkyl C₁₋₃        alkoxy, halo, and NR_(a)R_(b) wherein R_(a) and R_(b) are        independently H or C₁₋₃ alkyl;    -   R₃ and R₄ are independently selected from H, halo, cyano, C₁₋₅        alkyl hydroxy, C₂₋₄ acyl, C₁₋₄ alkoxy, and NR_(c)R_(d) wherein        R_(c), and R_(d) are independently H or C₁₋₃ alkyl provided that        R₃ and R₄ are not both H;    -   R₅ and R₆ are independently selected from H, C₁₋₈ alkyl and        substituted C₁₋₈ alkyl provided that R₅ and R₆ are not both H;    -   R₇ is selected from H, halo, C₁₋₈ alkyl and phenyl;    -   R₈ and R₉ are independently selected from halo, phenyl, C₁₋₉        alkyl C₁₋₈ alkoxy, C₂₋₉ alkenyl, C₂₋₉ alkenyloxy, C₃₋₇        cycloalkyl, C₃₋₇ cycloalkoxy, C₃₋₇cycloalkyl-C₁₋₇alkyl,        C₃₋₇cycloalkyl-C₁₋₇alkoxy, C₃₋₇cycloalkyloxy-C₁₋₆alkyl, and        C₃₋₇cycloalkyloxy-C₁₋₇alkoxy, or R₈ and R₉ together form C₁₋₉        alkylidenyl or C₃₋₉ alkenylidenyl; or R₈, R₉ and the carbon atom        to which they are attached together form C₃₋₇ cycloalkyl or 5-        or 6-membered heterocyclyl;    -   n is 0, 1 or 2; and    -   m is 0, 1 or 2;        or a pharmaceutically acceptable salt thereof.

The invention also features compositions that include one or morecompounds of Formula (I) and a pharmaceutical carrier or excipient.

These compositions and the methods below may further include additionalpharmaceutically active agents, such as lipid-lowering agents orblood-pressure lowering agents, or both.

Another aspect of the invention includes methods of using the disclosedcompounds or compositions in various methods for treating, preventing,or inhibiting the progression of, a condition directly or indirectlymediated by PPAR delta. Said condition includes, but is not limited to,diabetes, nephropathy, neuropathy, retinopathy, polycystic ovarysyndrome, hypertension, ischemia, stroke, irritable bowel disorder,inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome,hyper-LDL-cholesterolemia, dyslipidemia (including hypertriglyceridemia,hypercholesterolemia, mixed hyperlipidemia, andhypo-HDL-cholesterolemia), atherosclerosis, obesity, and other disordersrelated to lipid metabolism and energy homeostasis complicationsthereof.

One embodiment of the present invention is a method for treating a PPARmediated condition, such as a PPAR delta-mediated condition andoptionally one or more PPAR alpha- or PPAR gamma-mediated conditions,which PPAR alpha- or PPAR gamma-mediated condition(s) may be the same asor different from said PPAR delta-mediated condition, said methodcomprising administering to a patient in need of treatment apharmaceutically effective amount of a compound or composition describedherein.

Another embodiment of the present invention is a method for inhibitingthe onset and/or inhibiting the progression of a PPAR delta-mediatedcondition, said method comprising administering to a patient in need oftreatment a pharmaceutically effective amount of a compound orcomposition described herein.

Examples of conditions that can be treated with a PPAR-delta agonistinclude, without limitation, diabetes, cardiovascular diseases,Metabolic X Syndrome, hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity.Dyslipidemia includes hypertriglyceridemia, and mixed hyperlipidemia.For example, dyslipidemia (including hyperlipidemia) may be one or moreof the following conditions: low HDL (<35 or 40 mg/dl), hightriglycerides (>200 mg/dl), and high LDL (>150 mg/dl).

Examples of conditions that can be treated with a PPAR alpha-agonistinclude Syndrome X (or Metabolic Syndrome), dyslipidemia, high bloodpressure, obesity, impaired fasting glucose, insulin resistance, Type IIdiabetes, atherosclerosis, hypercholesterolemia, hypertriglyceridemia,and non-alcoholic steatohepatitis.

Additional features and advantages of the invention will become apparentfrom the detailed discussion, examples, and claims below.

DETAILED DESCRIPTION

The invention features compositions containing compounds of Formula (I)in the above Summary section, and methods of using them.

Preferred compounds of the invention are PPAR delta agonists that haveat least one and preferably two or three of the followingcharacteristics when administered to patients with hypercholesterolemia,hypertriglyceridemia, low-HDL-C, obesity, diabetes and/or Metabolic XSyndrome: 1) increasing HDL-C level, 2) lowering triglycerides, 3)lowering free fatty acids, and 4) decreasing insulin levels. Improvementin HDL-C and triglyceride levels is beneficial for cardiovascularhealth. In addition, decreased level of triglycerides and free fattyacids contributes to reduce obesity and ameliorate or prevent diabetes.

According to one aspect of the invention, the compounds of the inventionare dual PPAR compounds; in other words, they are both PPAR deltaagonists and PPAR alpha agonists, preferably where the compound's EC₅₀potency relating to PPAR delta is less than 0.2 μM and the potencyrelating to PPAR alpha is less than 3 μM. For example, more preferreddual PPAR alpha-delta agonists are those compounds having an EC₅₀potency relating to PPAR delta that is less than 0.03 μM and where thepotency relating to PPAR alpha is less than 1 μM.

According to another aspect of the invention, the compounds of theinvention are pan-PPAR agonists, namely, compounds having PPAR alpha,PPAR delta, and PPAR gamma agonist activity, preferably where the EC₅₀potency for PPAR delta is less than 0.2 μM; the potency for PPAR alphais less than 3 μM; and the potency for PPAR gamma is less than 1 μM.More preferred pan-PPAR agonists have an EC₅₀ potency for PPAR deltathat is less than 0.03 μM; a potency for PPAR alpha that is less than 1μM; and a potency for PPAR gamma that is less than 0.7 μM.

PPAR delta, being ubiquitously expressed, can act as a gateway receptorthat regulates the expression/activity of other nuclear receptors suchas other PPARs. For instance, PPAR delta has been shown to blockPPARγ-mediated adipogenesis and acyl-CoA oxidase expression; it has alsobeen shown to be associated with the nuclear receptor corepressors SMRT(silencing mediator for retinoid and thyroid hormone receptors), SHARP(SMART and histone deacetylase-associated repressor protein), and HDACs(histone deacetylase). Thus, conditions directly mediated by thesenuclear receptors, such as obesity and Type II diabetes, can beindirectly mediated by PPAR delta (See, for example, Shi et al., 2002,Proc Natl. Acad. Sci. USA, 99(5): 2613-2618).

Some aspects of the invention relate to treating hypertriglyceridemia,raising levels of HDL, lowering levels of LDL, and/or lowering totalcholesterol. Preferably, the methods of treatment are associated withimprovements in the extent, duration, or degree of side effects, such asedema, normally associated with other existing therapies.

The invention is further described below. The specification is arrangedas follows: A) Terms; B) Compounds; C) Synthesis; D) Formulation andAdministration; E) Use; F) Biological Examples; G) Other Embodiments;and claims.

A. Terms

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation, prevention, treatment, orthe delay of the onset or progression of the symptoms of the disease ordisorder being treated.

Conditions directly or indirectly mediated by PPAR delta include, butare not limited to, diabetes, cardiovascular diseases, Metabolic XSyndrome, hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, and obesity.

For therapeutic purposes, the term “jointly effective amount” as usedherein, means that amount of each active compound or pharmaceuticalagent, alone or in combination, that elicits the biological or medicinalresponse in a tissue system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of the symptoms of the disease or disorder beingtreated. For prophylactic purposes (i.e., inhibiting the onset orprogression of a disorder), the term “jointly effective amount” refersto that amount of each active compound or pharmaceutical agent, alone orin combination, that treats or inhibits in a subject the onset orprogression of a disorder as being sought by a researcher, veterinarian,medical doctor or other clinician. Thus, the present invention providescombinations of two or more drugs wherein, for example, (a) each drug isadministered in an independently therapeutically or prophylacticallyeffective amount; (b) at least one drug in the combination isadministered in an amount that is sub-therapeutic or sub-prophylactic ifadministered alone, but is therapeutic or prophylactic when administeredin combination with the second or additional drugs according to theinvention; or (c) both (or more) drugs are administered in an amountthat is sub-therapeutic or sub-prophylactic if administered alone, butare therapeutic or prophylactic when administered together.

Unless otherwise noted, as used herein and whether used alone or as partof a substituent group, “alkyl” and “alkoxy” include straight andbranched chains having 1 to 8 carbon atoms, such as C₁₋₆, C₁₋₄, C₃₋₈,C₂₋₅, or any other range, and unless otherwise noted, include bothsubstituted and unsubstituted moieties. For example, C₁₋₆alkyl radicalsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl,2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxyradicals are formed from the previously described straight or branchedchain alkyl groups. “Alkyl” and “alkoxy” include unsubstituted orsubstituted moieties with one or more substitutions, such as between 1and 5, 1 and 3, or 2 and 4 substituents. The substituents may be thesame (dihydroxy, dimethyl), similar (chloro, fluoro), or different(chlorobenzyl- or aminomethyl-substituted). Examples of substitutedalkyl include haloalkyl (such as fluoromethyl, chloromethyl,difluoromethyl, perchloromethyl, 2-bromoethyl, trifluoromethyl, and3-iodocyclopentyl), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl,2-hydroxypropyl), aminoalkyl (such as aminomethyl, 2-aminoethyl,3-aminopropyl, and 2-aminopropyl), alkoxylalkyl, nitroalkyl, alkylalkyl,cyanoalkyl, phenylalkyl, heteroarylalkyl, heterocyclylalkyl,phenoxyalkyl, heteroaryloxyalkyl (such as 2-pyridyloxyalkyl),heterocyclyloxy-alkyl (such as 2-tetrahydropyranoxy-alkyl),thioalkylalkyl (such as MeS-alkyl), thiophenylalkyl (such as phS-alkyl),carboxylalkyl, and so on. A di(C ₁₋₃alkyl)amino group includesindependently selected alkyl groups, to form, for example,methylpropylamino and isopropylmethylamino, in addition dialkylaminogroups having two of the same alkyl group such as dimethyl amino ordiethylamino.

The term “alkenyl” includes optionally substituted straight chain andbranched hydrocarbon radicals as above with at least one carbon-carbondouble bond (sp²). Alkenyls include ethenyl (or vinyl), prop-1-enyl,prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl,but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on.Hydrocarbon radicals having a mixture of double bonds and triple bonds,such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenylincludes cycloalkenyl. Cis and trans or (E) and (Z) forms are includedwithin the invention. “Alkenyl” may be substituted with one or moresubstitutions including, but not limited to, cyanoalkenyl, andthioalkenyl.

The term “alkynyl” includes optionally substituted straight chain andbranched hydrocarbon radicals as above with at least one carbon-carbontriple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, andpentynyls. Hydrocarbon radicals having a mixture of double bonds andtriple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein.Alkynyl does not include cycloalkynyl.

The term “Ac” as used herein, whether used alone or as part of asubstituent group, means acetyl (CH₃CO—). The term “acyl” as usedherein, refers to a substituent that has a carbonyl group (C═O) and oneor more alkyl or alkylene groups. For example, C₂₋₄ acyl includeswithout limitation, acetyl, CH₃CH₂—(C═O)—CH₂—, and CH₃ CH₂ CH₂(C═O)—.

The term “halogen” or “halo” shall include iodo, bromo, chloro andfluoro.

The terms “aryl” or “Ar” as used herein refer to an unsubstituted orsubstituted aromatic hydrocarbon ring system such as phenyl andnaphthyl. When the Ar or aryl group is substituted, it may have one tothree substituents which are independently selected from C₁-C₈ alkyl,C₁-C₈ alkoxy, fluorinated C₁-C₈ alkyl (e.g., trifluoromethyl),fluorinated C₁-C₈ alkoxy (e.g., trifluoromethoxy), halogen, cyano, C₁-C₈alkylcarbonyl such as acetyl, carboxyl, hydroxy, amino, nitro, C₁-C₄alkylamino (i.e., —NH—C₁-C₄ alkyl), C₁-C₄ dialkylamino (i.e., —N—[C₁-C₄alkyl]₂ wherein the alkyl groups can be the same or different), orunsubstituted, mono-, di- or tri-substituted phenyl wherein thesubstituents on the phenyl are independently selected from C₁-C₈ alkyl,C₁-C₈ alkoxy, fluorinated C₁-C₈ alkyl, fluorinated C₁-C₈ alkoxy,halogen, cyano, acetyl, carboxyl, hydroxy, amino, nitro, alkylamino,dialkylamino or five or six membered heteroaryl having 1-3 heteroatomsselected from N, O and S.

The term “heteroaryl” as used herein represents a stable, unsubstitutedor substituted five or six membered monocyclic or bicyclic aromatic ringsystem which consists of carbon atoms and from one to three heteroatomsselected from N, O and S. The heteroaryl group may be attached at anyheteroatom or carbon atom which results in the creation of a stablestructure. Examples of heteroaryl groups include, but are not limitedto, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzopyrazolyl,benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl,benzoxazolyl, furanyl, furazanyl, furyl, imidazolyl, indazolyl,indolizinyl, indolinyl, indolyl, isobenzofuranyl, isoindolyl,isothiazolyl, isoxazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, quinolyl,thiadiazolyl, thiazolyl, thiophenyl, or triazolyl. When the heteroarylgroup is substituted, the heteroaryl group may have one to threesubstituents including, but not limited to, C₁-C₈ alkyl, halogen, andaryl.

The term “heterocyclyl” includes optionally substituted nonaromaticrings having carbon atoms and at least one heteroatom (O, S, N) orheteroatom moiety (SO₂, CO, CONH, COO) in the ring. A heterocyclyl maybe saturated, partially saturated, nonaromatic, or fused. Examples ofheterocyclyl include cyclohexylimino, imidazolidinyl, imidazolinyl,morpholinyl, piperazinyl, piperidyl, pyridyl, pyranyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, and thienyl.

Unless otherwise indicated, heteroaryl and heterocyclyl may have avalence connecting it to the rest of the molecule through a carbon atom,such as 3-furyl or 2-imidazolyl, or through a heteroatom, such asN-piperidyl or 1-pyrazolyl. Preferably a monocyclic heterocyclyl hasbetween 5 and 7 ring atoms, or between 5 and 6 ring atoms; there may bebetween 1 and 5 heteroatoms or heteroatom moieties in the ring, andpreferably between 1 and 3, or between 1 and 2 heteroatoms or heteroatommoieties.

Heterocyclyl and heteroaryl also include fused, e.g., bicyclic, rings,such as those optionally fused with an optionally substitutedcarbocyclic or heterocyclic five- or six-membered aromatic ring. Forexample, “heteroaryl” includes an optionally substituted six-memberedheteroaromatic ring containing 1, 2 or 3 nitrogen atoms fused with anoptionally substituted five- or six-membered carbocyclic or heterocyclicaromatic ring. Said heterocyclic five- or six-membered aromatic ringfused with the said five- or six-membered aromatic ring may contain 1, 2or 3 nitrogen atoms where it is a six-membered ring, or 1, 2 or 3heteroatoms selected from oxygen, nitrogen and sulfur where it is afive-membered ring.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Where chemical moieties are combined, such as in ethoxymethyl orphenylethyl, the term is described in the direction from the peripheryto the connection point of the rest of the molecule. For example,ethoxymethyl is CH₃CH₂OCH₂— and phenylethyl is a phenyl group linked by—CH₂CH₂— to the rest of the molecule (and not a phenyl group linked tothe molecule with a CH₃CH₂ group as a substituent on the phenyl.) Whereparentheses are used, they indicate a peripheral substitution.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Compounds of the invention are further described in the next section.

B. Compounds

The present invention features compositions containing and methods ofusing compounds of Formula (I) as described above. Unless otherwisenoted, in Formula (I), each hydrocarbyl (alkyl alkenyl, alkynyl,cycloalkyl, cycloalkenyl, etc) or heterocarbyl (heterocyclyl,heteroaryl, heteroatom moiety such as sulfonyl, amino, amido etc.) maybe substituted or unsubstituted, for example, “alkyl” includessubstituted and unsubstituted alkyl and “heterocyclyl” and “aryl” and“alkoxy” and so on, may also be substituted or unsubstituted. Forexample, where R₄ is “methyl or methoxy”, unless otherwise indicated,these terms collectively include: methyl, methoxy, trifluoromethyl,trifluoromethoxy, difluoromethyl, difluoromethoxy, fluoromethyl,fluoromethoxy, chlorodifluoromethyl, chlorodifluoromethoxy,dichlorofluoromethyl, and dichlorofluoromethoxy, and so on.

Examples include those compounds wherein: (a) X is S or O; (b) X is acovalent bond; (c) X is O; (d) Y is O; (e) Y is S; (f) Z is O; (g) Z isCH or CH₂; (h) m is 1; (i) m is 2; (k) n is 1; (l) R₁ and R₂ areindependently selected from H, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, and Br;(m) R₁ and R₂ are independently selected from H, methyl, methoxy, F andCl; (n) R₃ and R₄ are independently selected from H, halo, cyano,acetyl, C₁₋₂ alkyl, and C₁₋₂ alkoxy; (o) R₃ is independently selectedfrom H, F, Cl, methyl, and methoxy; (p) R₄ is independently selectedfrom H, halo, cyano, C₁₋₂ alkyl, and C₁₋₂ alkoxy; (q) R₃ isindependently selected from H, halo, cyano, C₁₋₂ alkyl, and C₁₋₂ alkoxy,and R₄ is independently selected from F, Cl, methyl, and methoxy; (r) R₃is selected from methyl, methoxy, H, Cl, Br, I, OH, —CH(CF₃)₂, CF₃,—OCF₃, —N(CH₃)₂, —O—CH₂COOH, and —COCH₃, and R₄ is selected from H, Cl,and methyl; (s) R₈ and R₉ together form C₁₋₉ alkylidenyl or C₃₋₉alkenylidenyl, or R₈, R₉ and the carbon atom to which they attachtogether form C₃₋₇ cycloalkyl; (t) R₈ and R₉ are independently selectedfrom halo, phenyl, C₁₋₉ alkyl, C₁₋₈ alkoxy, C₂₋₉ alkenyl, C₂₋₉alkenyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy, C₃₋₇cycloalkyl-C₁₋₇alkyl,C₃₋₇cycloalkyl-C₁₋₇alkoxy, C₃₋₇cycloalkyloxy-C₁₋₆alkyl, andC₃₋₇cycloalkyloxy-C₁₋₇alkoxy; (u) R₃ is selected from H, F, Cl, methyl,and methoxy, and R₄ is selected from F, Cl, acetyl, methyl, methoxy,trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy,fluoromethyl, fluoromethoxy; (v) R₁ is selected from H, CF₃, methyl, Cl,and methoxy, and R₂ is selected from H, Cl, and methyl; (w) X is O and Yis O; (x) Z is O and Y is O; (y) R₁ is selected from H, CF₃, methyl, Cl,and methoxy, R₂ is selected from H, Cl, and methyl, R₃ is selected fromH, F, Cl, methyl, and methoxy, and R₄ is selected from F, Cl, methyl,and methoxy; (z) X is O, Y is O, R₃ is selected from H, F, Cl, methyl,and methoxy, and R₄ is selected from F, Cl, methyl, and methoxy; (z2) Zis O Y is O, R₃ is selected from H, F, Cl, methyl, and methoxy, and R₄is selected from F, Cl, methyl, and methoxy; (aa) R₁ is selected from H,CF₃, methyl, Cl, and methoxy, R₂ is selected from H, Cl, and methyl, R₃is selected from H, F, Cl, methyl, and methoxy, R₄ is selected from F,Cl, methyl, and methoxy, and R₅ and R₆ together form C₁₋₉ alkylidenyl orC₃₋₉ alkenylidenyl, or R₈, R₉ and the carbon atom to which they attachtogether form C₃₋₇ cycloalkyl; (bb) X is O, Y is O, Z is O, R₁ isselected from H, CF₃, methyl, Cl, and methoxy, R₂ is selected from H,Cl, and methyl, R₃ is selected from H, F, Cl, methyl, and methoxy, R₄ isselected from F, Cl, methyl, and methoxy, and R₈ and R₉ areindependently selected from halo, phenyl, C₁₋₉ alkyl, C₁₋₈ alkoxy, C₂₋₉alkenyl, C₂₋₉ alkenyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy,C₃₋₇cycloalkyl-C₁₋₇alkyl, C₃₋₇cycloalkyl-C₁₋₇alkoxy,C₃₋₇cycloalkyloxy-C₁₋₆alkyl, and C₃₋₇cycloalkyloxy-C₁₋₇alkoxy; (cc) X isO, Y is O, Z is O, R₁ is selected from H, CF₃, methyl, Cl, and methoxy,R₂ is selected from H, Cl, and methyl, R₃ is selected from H, F, Cl,methyl, and methoxy, and R₄ is selected from F, Cl, methyl, and methoxy;(dd) X is O, Y is O, Z is O, R₁ is selected from H, CF₃, methyl, Cl, andmethoxy, R₂ is selected from H, Cl, and methyl, R₃ is selected from H,F, Cl, methyl, and methoxy, R₄ is selected from F, Cl, methyl, andmethoxy, and R₈ and R₉ together form C₁₋₉ alkylidenyl or C₃₋₉alkenylidenyl, or R₈, R₉ and the carbon atom to which they attachtogether form C₃₋₇ cycloalkyl; (ee) X is O, Y is O, Z is O, R₁ isselected from H, CF₃, methyl, Cl, and methoxy, R₂ is selected from H,Cl, and methyl, R₃ is selected from H, F, Cl, methyl, and methoxy, R₄ isselected from F, Cl, methyl, and methoxy, and R₈ and R₉ areindependently selected from halo, phenyl, C₁₋₉ alkyl, C₁₋₈ alkoxy, C₂₋₉alkenyl, C₂₋₉ alkenyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy,C₃₋₇cycloalkyl-C₁₋₇alkyl, C₃₋₇cycloalkyl-C₁₋₇alkoxy,C₃₋₇cycloalkyloxy-C₁₋₆alkyl, and C₃₋₇cycloalkyloxy-C₁₋₇alkoxy; (ff) X isO, Y is O or S, Z is O, R₁ is selected from H, CF₃, methyl, Cl, andmethoxy, R₂ is selected from H, Cl, and methyl, R₃ is selected from H,F, Cl, methyl, and methoxy, R₄ is selected from F, Cl, methyl, andmethoxy, m is 1, and n is 1; (gg) X is O, Y is O or S, Z is O, R₁ isselected from H, CF₃, methyl, Cl, and methoxy, R₂ is selected from H,Cl, and methyl, R₃ is selected from H, F, Cl, methyl, and methoxy, R₄ isselected from F, Cl, methyl, and methoxy, m is 1, n is 1, and R₈ and R₉are independently selected from halo, phenyl, C₁₋₉ alkyl, C₁₋₈ alkoxy,C₂₋₉ alkenyl, C₂₋₉ alkenyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy,C₃₋₇cycloalkyl-C₁₋₇alkyl, C₃₋₇cycloalkyl-C₁₋₇alkoxy,C₃₋₇cycloalkyloxy-C₁₋₆alkyl, and C₃₋₇cycloalkyloxy-C₁₋₇alkoxy; (hh) R₅and R₆ are C₁₋₄ alkyl; (ii) R₅ and R₆ are methyl; (jj) R₅ and R₆ areboth methyl, both X and Z are O, R₇ is H, and R₈ and R₉ form ═CH₂; orcombinations of the above.

Compounds of the present invention further can be selected from:

2-Methyl-2-{2-methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-propionicacid

2-Methyl-2-{2-methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-allylsulfanyl]-phenoxy}-propionicacid

2-{4-[2-(4-Chloro-phenoxymethyl)-allylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionicacid

2-{4-[2-(3,4-Dichloro-phenoxymethyl)-allylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionicacid

2-{4-[2-(3-Fluoro-4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionicacid

2-{4-[2-(4-Isopropyl-phenoxymethyl)-allylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionicacid

2-Methyl-2-{2-methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allyloxy]-phenoxy}-propionicacid

2-Methyl-2-{2-methyl-4-[2-(4-trifluoromethoxy-phenoxymethyl)-allyloxy]-phenoxy}-propionicacid

2-{4-[2-(4-Chloro-phenoxymethyl)-allyloxy]-2-methyl-phenoxy}-2-methyl-propionicacid

2-{4-[2-(3,4-Dichloro-phenoxymethyl)-allyloxy]-2-methyl-phenoxy}-2-methyl-propionicacid

2-{4-[2-(3-Fluoro-4-trifluoromethyl-phenoxymethyl)-allyloxy]-2-methyl-phenoxy}-2-methyl-propionicacid

2-{4-[2-(4-Isopropyl-phenoxymethyl)-allyloxy]-2-methyl-phenoxy}-2-methyl-propionicacid

A preferred compound is listed in Table 1:

TABLE 1 Compound Number Structure 1

The pharmaceutical compounds of the invention include a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound described above.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

The invention provides the disclosed compounds and closely related,pharmaceutically acceptable forms of the disclosed compounds, such assalts, esters, amides, hydrates or solvated forms thereof; masked orprotected forms; and racemic mixtures, or enantiomerically or opticallypure forms.

Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁₋₈ alkyl, cycloalkyl, aryl, heteroaryl, ornon-aromatic heterocyclic) amino acid addition salts, esters, and amideswhich are within a reasonable benefit/risk ratio, pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. Representative saltsinclude hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. These may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylamine, trimethylamine, andethylamine. See example, S. M. Berge, et al., “Pharmaceutical Salts,” J.Pharm. Sci., 1977, 66:1-19, which is incorporated herein by reference.Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di(C₁₋₆ alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃ alkylprimary amines, and di(C₁₋₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇ alkyl,C₅₋₇ cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters.

The invention also includes disclosed compounds having one or morefunctional groups (e.g., amino, or carboxyl) masked by a protectinggroup. Some of these masked or protected compounds are pharmaceuticallyacceptable; others will be useful as intermediates. Syntheticintermediates and processes disclosed herein, and minor modificationsthereof, are also within the scope of the invention.

Hydroxyl Protecting Groups

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate)

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyldithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Amino Protecting Groups

Protection for the amino group includes carbamates, amides, and special—NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substitutedethyl carbamates, assisted cleavage carbamates, photolytic cleavagecarbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted Cleavage

Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-Type Derivatives

Examples of urea-type derivatives include phenothiazinyl-(10)-carbonylderivative, N′-p-toluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

Examples of amides include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-p-phenylbenzoyl.

Assisted Cleavage

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

Special—NH Protective Groups

Examples of special NH protective groups include

N-Alkyl and N-Aryl Amines

N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

Imine Derivatives

N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene,N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, andN—(N′,N′-dimethylaminomethylene).

Protection for the Carboxyl Group

Esters

Examples of esters include formate, benzoylformate, acetate,trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, benzoate.

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl,cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

Substituted Benzyl Esters

Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl anddi-t-butylmethylsilyl.

Activated Esters

Examples of activated esters include thiols.

Miscellaneous Derivatives

Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaaminocobalt(III) complex.

Stannyl Esters

Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

C. Synthesis

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Schemes A through G describe suggestedsynthetic routes. Using these Schemes, the guidelines below, and theexamples, a person of skill in the art may develop analogous or similarmethods for a given compound that are within the invention. Thesemethods are representative of the preferred synthetic schemes, but arenot to be construed as limiting the scope of the invention.

One skilled in the art will recognize that synthesis of the compounds ofthe present invention may be effected by purchasing an intermediate orprotected intermediate compounds described in any of the schemesdisclosed herein. One skilled in the art will further recognize thatduring any of the processes for preparation of the compounds in thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in “Protective Groups in Organic Synthesis”, John Wiley &Sons, 1991. These protecting groups may be removed at a convenient stageusing methods known from the art.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation. The compounds mayalso be resolved by formation of diastereomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column.

Examples using the preferred synthetic routes include Examples I and IICompounds analogous to the target compounds of these examples can bemade according to similar routes. The disclosed compounds are useful inbasic research and as pharmaceutical agents as described in the nextsection.

General Guidance

A preferred synthesis of Formula (I) is demonstrated in Schemes Athrough G.

In accordance with Scheme A, wherein R₁, R₂, R₅ and R₆ are as describedabove (except that R₅ and R₆ do not form spiro C₃₋₆ cycloalkyl or spiro5- or 6-membered heterocyclyl), phenol A1, a variety of which arecommercially available (such as 3-methylphenol, 2-ethylphenol,2-propylphenol, 2,3-dimethylphenol, 2-chlorophenol, 2,3-dichlorophenol,2-bromophenol, and 2-aminophenol), is alkylated to form phenoxyaceticacid ethyl ester A2 with a suitable haloacetic acid ester such asbromoacetic acid ethyl ester or 2-bromo-2-methylpropionic acid ethylester, in the presence of an appropriate base such as Cs₂CO₃, K₂CO₃, orNaH, in a suitable solvent such as CH₃CN or THF. Sulfonation of thephenoxyacetic acid ethyl ester A2 with an appropriate sulfonating agent,such as chlorosulfonic acid, occurs selectively at the para position toprovide 4-chlorosulfonylphenoxyacetic acid ethyl ester A3.Transformation of the sulfonylchloride A3 to benzenethiol A4 isaccomplished using a metal as a reducing agent, such as tin or zinc, inan acidic medium such as ethanol or dioxane.

In Schemes B, D, and E, R₈ and R₉ can be selected from, for example, H,C₁₋₈ alkyl, C₂₋₈ alkenyl, phenyl, halo, and cyano.

In Scheme B, Mitsunobu reaction of 1,3-diol B—B with phenol B-A providesalcohol B—C by employing a triarylphosphine such as triphenylphosphine,and an azodicarbonyl reagent such as diisopropyl azodicarboxylate, in asuitable solvent such as THF. Phenoxyacetic acid ethyl ester B-D isobtained in two steps: (1) conversion of the alcohol B—C to mesylateunder standard conditions by employing methanesulfonyl chloride andtriethylamine in an appropriate solvent such as CH₂Cl₂, and (2)alkylation of benzenethiol B-D, prepared according to Scheme A above,with the mesylate intermediate using a suitable base such as Cs₂CO₃,K₂CO₃, or NaH, in an appropriate solvent such as CH₃CN or THF, undernitrogen. Under standard saponification conditions phenoxyacetic acidethyl ester B-D is converted to acid B-E under nitrogen. The preferredhydrolysis conditions include using NaOH as a base in an aqueousalcoholic solvent system such as water-methanol, or using LiOH as a basein a milder water-THF system.

In Scheme C, R₈ and R₉ substituted malonate C-A is reduced topropane-1,3-diol C—B by using a suitable reducing agent such as lithiumaluminum hydride or diisobutylaluminum hydride. After propane-1,3-diolC—B is converted to dimesylate C—C by using methanesulfonyl chloride andtriethylamine in an appropriate solvent such as CH₂Cl₂, C—C reacts withphenol B-A in the presence of a suitable base such as Cs₂CO₃, K₂CO₃, orNaH in an appropriate solvent such as CH₃CN or THF to produce mesylateC-D. Phenoxyacetic acid ethyl ester C-E is obtained by alkylation ofbenzenethiol A-D, prepared according to Scheme A above, with themesylate C-D using a suitable base such as Cs₂CO₃, K₂CO₃, or NaH in anappropriate solvent such as CH₃CN or THF under nitrogen. Under standardsaponification conditions phenoxyacetic acid ethyl ester C-E isconverted to acid Ia under nitrogen. The preferred hydrolysis conditionsinclude using NaOH as a base in an aqueous alcoholic solvent system suchas water-methanol, or using LiOH as a base in a milder water-THF system.

In accordance with Scheme D, wherein R₈′ and R₉′ are independentlyselected from H and C₁₋₆ alkyl aldehyde D-B could be prepared in twosteps by methylation of acid D-A using (trimethylsilyl)diazomethane as amethylating agent followed by reduction of the methyl ester intermediatewith a suitable reducing agent such as diisobutylaluminum hydride.Aldehyde D-B is transformed to epoxide D-C by reacting withdimethylsulfonium methylide, which is generated in-situ from treatmentof trimethylsulfonium iodide with a strong base such as DMSO anion.Epoxide ring opening of D-C with benzenethiol A-D in the presence of acatalytic amount of tetrabutylammonium fluoride furnishes alcohol D-D,which is oxidized to ketone D-E under mild oxidation conditions by usingacetic anhydride and dimethyl sulfoxide. Several types of olefination ofketone D-E may be carried out to provide alkene D-F. For example, Wittigreaction and olefination of D-E with Tebbe reagent will all give D-F.Finally, saponification of ethyl ester D-F under standard conditionsgives acid Ib.

Scheme E shows another route to prepare acid E-E as demonstrated inScheme B. In Scheme E, epoxide E-B is obtained by treatment of phenolB-A with an appropriate base such as cesium carbonate followed byalkylation with 2-chloromethyl-oxirane E-A. Epoxide ring opening of E-Bwith benzenethiol A-D, prepared in Scheme A above, in the presence of acatalytic amount of tetrabutylammonium fluoride furnishes alcohol E-C,which is oxidized to ketone E-D under mild oxidation conditions by usingacetic anhydride and dimethyl sulfoxide. Several types of olefination ofketone E-D may be carried out to provide alkene B-D. For example, Wittigreaction and olefination of E-D with Tebbe reagent will all give B-D.Finally, saponification of ethyl ester B-D under standard conditionsgives acid Ic.

In accordance with Scheme F, (4-hydroxyphenyl)acetic acid F-A, a varietyof which are commercially available (such as 3-bromo-4-hydroxyphenylacetic acid, 3-chloro-4-hydroxyphenyl acetic acid,3-fluoro-4-hydroxyphenyl acetic acid, 4-hydroxy-3-methoxyphenyl aceticacid, and 4-hydroxy-3-nitrophenyl acetic acid), is methylated to form(4-hydroxyphenyl)acetic acid methyl ester F-B in methanol in thepresence of a catalytic amount of a suitable acid such as sulfuric acidor hydrochloric acid. The phenol F-B is converted to(4-dimethylthiocarbamoyloxyphenyl)acetic acid methyl ester F-C byreacting with dimethylthiocarbamoyl chloride in the presence of someappropriate bases such as triethylamine and 4-(dimethylamino)pyridine.At high temperature, in the preferred range of 250 to 300° C., F-C isrearranged to (4-dimethylcarbamoylsulfanylphenyl)acetic acid methylester F-D in a high boiling point solvent such as tetradecane. Bytreatment with a suitable base such as sodium methoxide F-D istransformed to (4-mercaptophenyl)acetic acid methyl ester F-E.

In Scheme G, acetic acid methyl ester G-A is obtained by alkylation ofbenzenethiol F-E, prepared according to Scheme F above, with mesylateC-D using a suitable base such as Cs₂CO₃, K₂CO₃, or NaH in anappropriate solvent such as CH₃CN or THF under nitrogen. Under standardsaponification conditions methyl ester G-A is hydrolyzed to acid Id.

EXAMPLES Example I

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-aceticacid

(4-Chlorosulfonyl-2-methyl-phenoxy)-acetic acid ethyl ester

To a flask containing chlorosulfonic acid (15.0 mL, 226 mmol) at 4° C.was added ethyl (2-methylphenoxy)acetate 1-A (10.0 g, 51.6 mmol) slowly.The mixture was stirred at 4° C. for 30 min and room temperature for 2h, and then poured into ice water. The precipitated white solid wasfiltered, washed with water, and dried under vacuum overnight to provide14.0 g (93%) of 1-B as a white solid; ¹H NMR (300 MHz, CDCl₃) δ7.87-7.84 (m, 2 H), 6.80 (d, J=9.5 Hz, 1 H), 4.76 (s, 2 H), 4.29 (q,J=7.1 Hz, 2 H), 2.37 (s, 3 H), 1.31 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 315(M+Na⁺).

(4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester

To a solution of 1-B (4.70 g, 16.1 mmol) in EtOH (20 mL) was added asolution of 4.0 M HCl in dioxane (20 mL) followed by 100 mesh tin powder(9.80 g, 82.6 mmol) portionwise. The mixture was refluxed for 2 h,poured into CH₂Cl₂/ice (100 mL), and filtered. The filtrate wasseparated, and the aqueous layer was extracted with CH₂Cl₂. The combinedorganic phases were washed with water, dried, and concentrated to give3.56 g (98%) of 1-C as a yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 7.14-7.03(m, 2 H), 6.59 (d, J=8.4 Hz, 1 H), 4.60 (s, 2 H), 4.25 (q, J=7.1 Hz, 2H), 2.24 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H).

2-(4-Trifluoromethyl-phenoxymethyl)-prop-2-en-1-ol

To a mixture of 4-trifluoromethylphenol (49.0 g, 302 mmol),2-methylene-1,3-propanediol (40.0 g, 454 mmol), and diisopropylazodicarboxylate (67.4 g, 333 mmol) in CH₂Cl₂ (400 mL) at 0° C. wascharged with a solution of triphenylphosphine (87.2 g, 333 mmol) inCH₂Cl₂ (400 mL) dropwise. After the mixture was stirred at 0° C. andthen allowed to warm up to room temperature overnight, CH₂Cl₂ wasevaporated under reduced pressure. To the residue was added Et₂O andhexane, and the mixture was cooled to 0° C. The precipitated solid wasfiltered, and the filtrate was concentrated and column chromatographed(EtOAc/hexane: ¼) to give 35.2 g (50%) of 2-A; ¹H NMR (300 MHz, CDCl₃) δ7.55 (d, J=8.6 Hz, 2 H), 6.99 (d, J=8.6 Hz, 2 H), 5.33 (d, J=0.9 Hz, 1H), 5.29 (d, J=0.9 Hz, 1 H), 4.65 (s, 2 H), 4.27 (d, J=6.0 Hz, 2 H).

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-aceticacid ethyl ester

General Procedure 1 for the Formation Of Thioether

To a solution of 2-A (18.1 g, 78.2 mmol) in CH₂Cl₂ (400 mL) at 0° C.were added Et₃N (23.0 mL, 165 mmol) and methanesulfonyl chloride (13.4g, 117 mmol). The mixture was stirred at 0° C. for 1 h and roomtemperature overnight and diluted with saturated NaHCO₃ (100 mL). Theorganic layer was separated and the aqueous layer was extracted withCH₂Cl₂ (×3). The combined organic phases were dried and concentrated toprovide 24.2 g of the crude product.

A mixture of the above crude product,(4-mercapto-2-methyl-phenoxy)acetic acid ethyl ester 1-C (21.2 g, 93.8mmol), and Cs₂CO₃ (76.2 g, 234 mmol) in CH₃CN (290 mL) was stirred atroom temperature for 2 h. Water was added and the mixture was extractedwith CH₂Cl₂. The combined organic layers were dried, concentrated, andcolumn chromatographed (EtOAc/hexane: 1/10) to provide 28.8 g (84%) of2-B; ¹H NMR (300 MHz, CDCl₃) δ 7.53 (d, J=8.7 Hz, 2 H), 7.20 (s, 1 H),7.16 (dd, J=8.4, 2.2 Hz, 1 H), 6.96 (d, J=8.6 Hz, 2 H), 6.59 (d, J=8.4Hz, 1 H), 5.13 (d, J=0.9 Hz, 1 H), 4.98 (s, 1 H), 4.65 (s, 2 H), 4.60(s, 2 H), 4.26 (q, J=7.1 Hz, 2 H), 3.56 (s, 2 H), 2.24 (s, 3 H), 1.29(t, J=7.1 Hz, 3 H); MS (ES) m/z: 463 (M+Na⁺).

{2-Methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-aceticacid

General Procedure 2 for the Hydrolysis of the Ethyl and Methyl Esters

To a solution of 2-B (28.8 g, 65.5 mmol) in THF (576 mL) at 0° C. underN₂ was added 1.0 M LiOH (131 mL, 131 mmol). After stirring at 0° C. for45 min and at room temperature for 2.5 h, the mixture was cooled to 0°C., acidified with 1 M HCl, and extracted with EtOAc (×3). The extractswere dried, concentrated, and purified by column chromatography to give26.7 g (99%) of{2-methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-aceticacid; ¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.6 Hz, 2 H), 7.21 (s, 1 H),7.17 (dd, J=8.4, 2.2 Hz, 1 H), 6.95 (d, J=8.6 Hz, 2 H), 6.62 (d, J=8.4Hz, 1 H), 5.14 (d, J=1.0 Hz, 1 H), 4.99 (d, J=1.0 Hz, 1 H), 4.65 (s, 4H), 3.57 (s, 2 H), 2.23 (s, 3 H); MS (ES) m/z: 435 (M+Na⁺).

Example II

2-Methyl-2-{2-methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-propionicacid

To a solution of 2-bromo-2-methyl-propionic acid ethyl ester (8.27 mL,64 mmol) and o-methyl-phenol (7.60 g, 70.2 mmol) in dioxane (100 mL) wasadded Cs₂CO₃ (31.25 g, 96 mmol). The mixture was refluxed at 100° C. for4 hours. After cooling down, the solvent was evaporated under vacuum.The residue was dissolved in ether and then the solution was washed with1 N NaOH. After drying, the solution was concentrated to give 9.69 g(68%) 3-A; ¹H NMR (300 MHz, CDCl₃) δ 7.13 (d, J=7.3 Hz, 1 H), 7.03 (t,J=7.6 Hz, 1 H), 6.87 (t, J=7.3 Hz, 1 H), 6.66 (d, J=8.2 Hz, 1 H), 4.24(q, J=7.1 Hz, 2 H), 2.23 (s, 3 H), 1.59 (s, 6 H), 1.25 (t, J=7.1 Hz).

2-(4-Chlorosulfonyl-2-methyl-phenoxy)-2-methyl-propionic acid ethylester

CISO₃H (15.2 mL, 0.229 mol) was slowly added to 3-A (11.3 g, 0.051 mol)at 0° C., The temperature was allowed to warm to room temperature andstir for 1 hour. Upon stirring, the reaction mixture was poured intoice. The solid was filtered and vacuum dried to give 7.7 g (47%) of 3-B;¹H NMR (300 MHz, CDCl₃) δ 7.82 (d, J=2.5 Hz, 1 H), 7.75 (dd, J=8.9, 2.5Hz, 1 H), 6.67 (d, J=8.8 Hz, 1 H), 4.23 (q, J=7.1 Hz, 2 H), 2.31 (s, 3H), 1.70 (s, 6 H), 1.22 (t, J=7.1 Hz); MS (ES) m/z: 343 (M+Na⁺).

2-(4-Mercapto-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester

To a solution of 3-B (2.0 g, 6.25 mmol) in EtOH (7.8 mL) was addedHCl-dioxane (4 M, 7.8 mL, 31.2 mmol) and tin powder (3.7 g, 31.2 mmol).The mixture was refluxed for 3 hours and then poured into ice. Theaqueous solution was extracted with CH₂Cl₂ (50 mL×3). The organic layerswere combined and dried over Na₂SO₄. After filtration, the solution wasconcentrated to give 3.37 g (˜100%) 3-C; ¹H NMR (300 MHz, CDCl₃) δ 7.12(d, J=2.0 Hz, 1 H), 7.00 (dd, J=8.4, 2.4 Hz, 1 H), 6.56 (d, J=8.4 Hz, 1H), 4.23 (q, J=7.1 Hz, 2 H), 3.31 (s, 1 H), 2.18 (s, 3 H), 1.57 (s, 6H), 1.25 (t, J=7.1 Hz); MS (ES) m/z: 255 (M+H⁺).

2-Methyl-2-{2-methyl-4-[2-(4-trifluoromethyl-phenoxymethyl)-allylsulfanyl]-phenoxy}-propionicacid ethyl ester

To a solution of 2-A (139 mg, 0.6 mmol) in CH₂Cl₂ (3 mL) at 0° C. wasadded Et₃N (0.18 mL, 1.28 mmol) and then MeSO₂Cl (0.1 g, 0.9 mmol). Themixture was stirred at 0° C. for 10 minutes and then room temperaturefor 2 hours. After concentration, the crude product was purified bycolumn chromatography (50% CH₂Cl₂ in hexanes) to give 188 mg of crudeintermediate.

The above crude intermediate, 3-C (183 mg, 0.72 mmol) and Cs₂CO₃ (469mg, 1.44 mmol) in acetonitrile was stirred at room temperature for 3 h.Water and Et₂O were added, the organic phase was separated, and theaqueous phase was extracted with Et₂O. The combined organic layers weredried, concentrated and column chromatographed (hexane/EtOAc: 10:1) toprovide 140 mg (42%) of 3-D; 1H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.6Hz, 2H), 7.18 (s, 1H), 7.07 (dd, J=8.5, 2.4 Hz, 1H), 6.96 (d, J=8.5 Hz,2H), 6.57 (d, J=8.5 Hz, 1H), 5.12 (s, 1H), 4.96 (s, 1H), 4.65 (s, 2H),4.22 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.17 (s, 3H), 1.58 (s, 6H), 1.28(t, J=7.1 Hz, 3H); MS (ES) m/z: 491 (M+Na⁺).

A mixture of 3-D (128 mg, 0.27 mmol), THF (0.7 mL), MeOH (1.4 mL) and 3N NaOH (0.7 mL) was stirred at 25° C. for 4 h. 1 N HCl and Et₂O wereadded, the organic phase was separated, and the aqueous phase wasextracted with Et₂O. The combined organic layers were dried,concentrated and column chromatographed (CH₂Cl₂/MeOH: 10:1) to provide57 mg (47%) of Compound 1; ¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=8.6 Hz,2H), 7.20 (d, J=1.8 Hz, 1H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 6.96 (d,J=8.6 Hz, 2H), 6.73 (d, J=8.4 Hz, 1H), 5.15 (s, 1H), 5.02 (s, 1H), 4.65(s, 2H), 3.59 (s, 2H), 2.18 (s, 3H), 1.59 (s, 6H)); MS (ES) m/z: 439(M−H⁺).

D. Formulation and Administration

The present compounds are PPAR delta agonists and are therefore usefulin treating or inhibiting the progression of PPAR delta mediatedconditions, such as diabetes, cardiovascular diseases, Metabolic XSyndrome, hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipidemia, atherosclerosis, obesity, andcomplications thereof. For instance, complications of diabetes includesuch conditions as neuropathy, nephropathy, and retinopathy.

The invention features a method for treating a subject with a PPAR deltamediated disease, said method comprising administering to the subject atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of the invention. The invention also provides amethod for treating or inhibiting the progression of diabetes orimpaired glucose tolerance in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount of apharmaceutical composition comprising a compound of the invention.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. To prepare thesepharmaceutical compositions, an effective amount of a particularcompound, in base or acid addition salt form, as the active ingredientis intimately mixed with a pharmaceutically acceptable carrier.

A carrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for oral administration or parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. These include water, glycols,oils, alcohols and the like in the case of oral liquid preparations suchas suspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. In view oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are generally employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Such additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of the compounds of formulaI, due to their increased water solubility over the corresponding baseform, are more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification herein refers to physically discrete units suitable asunitary dosages, each unit containing a predetermined quantity of activeingredient calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. Examples of suchdosage unit forms are tablets (including scored or coated tablets),capsules, pills, powder packets, wafers, injectable solutions orsuspensions, teaspoonfuls, tablespoonfuls and the like, and segregatedmultiples thereof.

Pharmaceutically acceptable acid addition salts include thetherapeutically active non-toxic acid addition salts of disclosedcompounds. The latter can conveniently be obtained by treating the baseform with an appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, palmoic andthe like acids. The term addition salt also comprises the solvates whichthe disclosed compounds, as well as the salts thereof, are able to form.Such solvates are for example hydrates, alcoholates and the like.Conversely the salt form can be converted by treatment with alkali intothe free base form.

Stereoisomeric forms define all the possible isomeric forms which thecompounds of Formula (I) may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically isomeric forms, said mixtures containingall diastereomers and enantiomers of the basic molecular structure. Morein particular, stereogenic centers may have the (R)- or(S)-configuration; substituents on bivalent cyclic saturated radicalsmay have either the cis- or trans-configuration. The inventionencompasses stereochemically isomeric forms including diastereoisomers,as well as mixtures thereof in any proportion of the disclosedcompounds. The disclosed compounds may also exist in their tautomericforms. Such forms although not explicitly indicated in the above andfollowing formulae are intended to be included within the scope of thepresent invention.

Those of skill in the treatment of disorders or conditions mediated bythe PPAR delta could easily determine the effective daily amount fromthe test results presented hereinafter and other information. In generalit is contemplated that a therapeutically effective dose would be from0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01 mg/kg to0.5 mg/kg body weight. It may be appropriate to administer thetherapeutically effective dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may beformulated as unit dosage forms, for example, containing 0.05 mg to 250mg or 750 mg, and in particular 0.5 to 50 mg of active ingredient perunit dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25mg, and 35 mg dosage forms. Compounds of the invention may also beprepared in time-release or subcutaneous or transdermal patchformulations. Disclosed compound may also be formulated as a spray orother topical or inhalable formulations.

The exact dosage and frequency of administration depends on theparticular compound of Formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the patient may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated patient and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned herein are therefore only guidelines.

The next section includes detailed information relating to the use ofthe disclosed compounds and compositions.

E. Use

The compounds of the present invention are pharmaceutically active, forexample, as PPAR delta agonists and preferably as PPAR alpha/delta dualagonists. According to one aspect of the invention, the compounds arepreferably selective PPAR delta agonists, having an activity index(e.g., PPAR delta potency over PPAR alpha/gamma potency) of 10 or more,and preferably 15, 25, 30, 50 or 100 or more. According to anotheraspect, the compounds are dual PPAR alpha and PPAR delta agonists.

According to the invention, the disclosed compounds and compositions areuseful for the amelioration of symptoms associated with, the treatmentof, and the prevention of, the following conditions and diseases: phaseI hyperlipidemia, pre-clinical hyperlipidemia, phase II hyperlipidemia,hypertension, CAD (coronary artery disease), atherosclerosis, coronaryheart disease, cardiovascular disease, hypercholesteremia, andhypertriglyceridemia, type II diabetes, insulin resistance, impairedglucose tolerance, dyslipidemia, and low HDL-C. Preferred compounds ofthe invention are useful in lowering serum levels of low-densitylipoproteins (LDL), intermediate density lipoprotein (IDL), and/orsmall-density LDL and other atherogenic molecules, or molecules thatcause atherosclerotic complications, thereby reducing cardiovascularcomplications. Preferred compounds also are useful in elevating serumlevels of high-density lipoproteins (HDL), in lowering serum levels oftriglycerides, LDL, and/or free fatty acids. It is also desirable tolower fasting plasma glucose (FPG)/HbA1c.

PPAR alpha-mediated diseases include Syndrome X (or Metabolic Syndrome),dyslipidemia, high blood pressure, obesity, insulin resistance, impairedfasting glucose, type II diabetes, atherosclerosis, non-alcoholicsteatohepatitis, hypercholesterolemia, hypertriglyceridemia, and lowHDL-C.

According to one aspect of the invention, the disclosed compounds may beused in a method for treating or inhibiting the progression of aPPAR-delta mediated condition and, optionally, an additional PPAR-alphamediated condition, said method comprising administering to a patient inneed of treatment a pharmaceutically effective amount of a compositionof the invention.

Another aspect of the invention is a method of use wherein thePPAR-delta mediated condition is selected from hyperlipidemia,atherosclerosis, cardiovascular disease, hypercholesteremia, type IIdiabetes, insulin resistance, and impaired glucose tolerance, and otherconditions disclosed herein; and a PPAR-alpha mediated condition isselected from Syndrome X (or Metabolic Syndrome), dyslipidemia, highblood pressure, obesity, and impaired fasting glucose, insulinresistance, type II diabetes and other conditions disclosed herein.

A further aspect of the invention is a method for treating at least onePPAR-delta mediated condition and at least one PPAR-alpha mediatedcondition in a patient, said method comprising administering to apatient in need of treatment a pharmaceutically effective amount of acomposition of the invention.

The invention also features pharmaceutical compositions which include,without limitation, one or more of the disclosed compounds, andpharmaceutically acceptable carrier or excipient.

1. Dosages

Those skilled in the art will be able to determine, according to knownmethods, the appropriate dosage for a patient, taking into accountfactors such as age, weight, general health, the type of symptomsrequiring treatment, and the presence of other medications. In general,an effective amount will be between 0.1 and 1000 mg/kg per day,preferably between 1 and 300 mg/kg body weight, and daily dosages willbe between 10 and 5000 mg for an adult subject of normal weight.Capsules, tablets or other formulations (such as liquids and film-coatedtablets) may be of between 5 and 200 mg, such as 10, 15, 25, 35, 50 mg,60 mg, and 100 mg and can be administered according to the disclosedmethods.

2. Formulations

Dosage unit forms include tablets, capsules, pills, powders, granules,aqueous and nonaqueous oral solutions and suspensions, and parenteralsolutions packaged in containers adapted for subdivision into individualdoses. Dosage unit forms can also be adapted for various methods ofadministration, including controlled release formulations, such assubcutaneous implants. Administration methods include oral, rectal,parenteral (intravenous, intramuscular, subcutaneous), intracisternal,intravaginal, intraperitoneal, intravesical, local (drops, powders,ointments, gels or cream), and by inhalation (a buccal or nasal spray).

Parenteral formulations include pharmaceutically acceptable aqueous ornonaqueous solutions, dispersion, suspensions, emulsions, and sterilepowders for the preparation thereof. Examples of carriers include water,ethanol, polyols (propylene glycol, polyethylene glycol), vegetableoils, and injectable organic esters such as ethyl oleate. Fluidity canbe maintained by the use of a coating such as lecithin, a surfactant, ormaintaining appropriate particle size. Carriers for solid dosage formsinclude (a) fillers or extenders, (b) binders, (c) humectants, (d)disintegrating agents, (e) solution retarders, (f) absorptionaccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and(j) propellants.

Compositions may also contain adjuvants such as preserving, wetting,emulsifying, and dispensing agents; antimicrobial agents such asparabens, chlorobutanol, phenol, and sorbic acid; isotonic agents suchas a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

3. Combination Therapy

The compounds of the present invention may be used in combination withother pharmaceutically active agents. These agents include lipidlowering agents, and blood pressure lowering agents such as statin drugsand the fibrates.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that treats or inhibitsin a subject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician. Thus, thepresent invention provides combinations of two or more drugs wherein,for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both (ormore) drugs are administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

Anti-diabetic agents include thiazolidinedione and non-thiazolidinedioneinsulin sensitizers, which decrease peripheral insulin resistance byenhancing the effects of insulin at target organs and tissues.

Some of the following agents are known to bind and activate the nuclearreceptor peroxisome proliferator-activated receptor-gamma (PPARγ) whichincreases transcription of specific insulin-responsive genes. Examplesof PPAR-gamma agonists are thiazolidinediones such as:

-   -   (1) rosiglitazone        (2,4-thiazolidinedione,5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-,        (Z)-2-butenedioate (1:1) or        5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as AVANDIA; also known as BRL 49653, BRL 49653C, BRL        49653c, SB 210232, or rosiglitazone maleate);    -   (2) pioglitazone (2,4-thiazolidinedione,        5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-,        monohydrochloride, (+−)- or        5-((4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as ACTOS, ZACTOS, or GLUSTIN; also known as AD 4833, U        72107, U 72107A, U 72107E, pioglitazone hydrochloride (USAN));    -   (3) troglitazone        (5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl)methyl)-2,4-thiazolidinedione,        known as NOSCAL, REZULIN, ROMOZIN, or RELAY; also known as CI        991, CS 045, GR 92132, GR 92132×);    -   (4) isaglitazone        ((+)-5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-thiazoli        dinedione or        5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl-2,4-thiazolidinedione        or 5-(6-(2-fluorobenzyloxy)        naphthalen-2-ylmethyl)thiazolidine-2,4-dione, also known as        MCC-555 or neoglitazone); and    -   (5) 5-BTZD.

Additionally, the non-thiazolidinediones that act as insulin sensitizingagents include, but are not limited to:

-   -   (1) JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU 182716:        isoxazolidine-3,5-dione,        4-((4-(2-phenyl-5-methyl)-1,3-oxazolyl)ethylphenyl-4)methyl-);    -   (2) KRP-297        (5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-(trifluoromethyl)benzyl)benzamide        or        5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide);        and    -   (3) Farglitazar (L-tyrosine,        N-(2-benzoylphenyl)-o-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-        or        N-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl)-L-tyrosine,        or GW2570 or GI-262570).

Other agents have also been shown to have PPAR modulator activity suchas PPAR gamma, SPPAR gamma, and/or PPAR delta/gamma agonist activity.Examples are listed below:

-   -   (1) AD 5075;    -   (2) R        119702((+−)-5-(4-(5-Methoxy-1H-benzimidazol-2-ylmethoxy)benzyl)thiazolin-2,4-dione        hydrochloride, or Cl 1037 or CS 011);    -   (3) CLX-0940 (peroxisome proliferator-activated receptor alpha        agonist/peroxisome proliferator-activated receptor gamma        agonist);    -   (4) LR-90 (2,5,5-tris(4-chlorophenyl)-1,3-dioxane-2-carboxylic        acid, PPA        delta/γ agonist);    -   (5) Tularik (PPA        γ agonist);    -   (6) CLX-0921 (PPA        γ agonist);    -   (7) CGP-52608 (PPA        agonist);    -   (8) GW-409890 (PPA        agonist);    -   (9) GW-7845 (PPA        agonist);    -   (10) L-764406 (PPA        agonist);    -   (11) LG-101280 (PPA        agonist);    -   (12) LM-4156 (PPA        agonist);    -   (13) Risarestat (CT-112);    -   (14) YM 440 (PPA        agonist);    -   (15) AR-H049020 (PPA        agonist);    -   (16) GW 0072        (4-(4-((2S,5S)-5-(2-(bis(phenylmethyl)amino)-2-oxoethyl)-2-heptyl-4-oxo-3-thiazolidinyl)butyl)benzoic        acid);    -   (17) GW 409544 (GW-544 or GW-409544);    -   (18) NN 2344 (DRF 2593);    -   (19) NN 622 (DRF 2725);    -   (20) AR-H039242 (AZ-242);    -   (21) GW 9820 (fibrate);    -   (22) GW 1929 (N-(2-benzoylphenyl)-O—        (2-(methyl-2-pyridinylamino)ethyl)-L-tyrosine, known as GW 2331,        PPA        alpha/γ agonist);    -   (23) SB 219994        ((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)benzenepropanoic        acid or        3-(4-(2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2 (S)—        (2,2,2-trifluoroethoxy)propionic acid or benzenepropanoic        acid,4-(2-(2-benzoxazolylmethylamino)ethoxy)-alpha-(2,2,2-trifluoroethoxy)        (alphaS)-, PPA        alpha/γ agonist);    -   (24) L-796449 (PPA        alpha/γ agonist);    -   (25) Fenofibrate (Propanoic acid,        2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-, 1-methylethyl ester,        known as TRICOR, LIPCOR, LIPANTIL, LIPIDIL MICRO PPA        alpha agonist);    -   (26) GW-9578 (PPA        alpha agonist);    -   (27) GW-2433 (PPA        alpha/γ agonist);    -   (28) GW-0207 (PPA        γ agonist);    -   (29) LG-100641 (PPA        γ agonist);    -   (30) LY-300512 (PPA        γ agonist);    -   (31) NID525-209 (NID-525);    -   (32) VDO-52 (VDO-52);    -   (33) LG 100754 (peroxisome proliferator-activated receptor        agonist);    -   (34) LY-510929 (peroxisome proliferator-activated receptor        agonist);    -   (35) bexarotene        (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl)benzoic        acid, known as TARGRETIN, TARGRETYN, TARGREXIN; also known as        LGD 1069, LG 100069, LG 1069, LDG 1069, LG 69, RO 264455); and    -   (36) GW-1536 (PPAR alpha/γ agonist).

(B) Other insulin sensitizing agents include, but are not limited to:

-   -   (1) INS-1 (D-chiro inositol or        D-1,2,3,4,5,6-hexahydroxycyclohexane);    -   (2) protein tyrosine phosphatase 1 B (PTP-1B) inhibitors;    -   (3) glycogen synthase kinase-3 (GSK3) inhibitors;    -   (4) beta 3 adrenoceptor agonists such as ZD 2079        ((R)—N-(2-(4-(carboxymethyl)phenoxy)ethyl)-N-(2-hydroxy-2-phenethyl)        ammonium chloride, also known as ICI D 2079) or AZ 40140;    -   (5) glycogen phosphorylase inhibitors;    -   (6) fructose-1,6-bisphosphatase inhibitors;    -   (7) chromic picolinate, vanadyl sulfate (vanadium oxysulfate);    -   (8) KP 102 (organo-vanadium compound);    -   (9) chromic polynicotinate;    -   (10) potassium channel agonist NN 414;    -   (11) YM 268 (5,5′-methylene-bis(1,4-phenylene)bismethylenebis        (thiazolidine-2,4-dione);    -   (12) TS 971;    -   (13) T 174        ((+−)-5-(2,4-dioxothiazolidin-5-ylmethyl)-2-(2-naphthylmethyl)benzoxazole);    -   (14) SDZ PGU 693        ((+)-trans-2(S—((4-chlorophenoxy)methyl)-7alpha-(3,4-dichlorophenyl)tetrahydropyrrolo        (2,1-b)oxazol-5(6H)— one);    -   (15) S 15261        ((−)-4-(2-((9H-fluoren-9-ylacetyl)amino)ethyl)benzoic acid        2-((2-methoxy-2-(3-(trifluoromethyl)phenyl)ethyl)amino) ethyl        ester);    -   (16) AZM 134 (Alizyme);    -   (17) ARIAD;    -   (18) R 102380;    -   (19) PNU 140975 (1-(hydrazinoiminomethyl)hydrazino)acetic acid;    -   (20) PNU 106817 (2-(hydrazinoiminomethyl)hydrazino)acetic acid;    -   (21) NC 2100        (5-((7-(phenylmethoxy)-3-quinolinyl)methyl)-2,4-thiazolidinedione;    -   (22) MXC 3255;    -   (23) MBX 102;    -   (24) ALT 4037;    -   (25) AM 454;    -   (26) JTP 20993        (2-(4-(2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy)benzyl)-malonic        acid dimethyl diester);    -   (27) Dexlipotam (5 (R)— (1,2-dithiolan-3-yl)pentanoic acid, also        known as (R)-alpha lipoic acid or (R)-thioctic acid);    -   (28) BM 170744 (2,2-Dichloro-12-(p-chlorophenyl)dodecanoic        acid);    -   (29) BM 152054        (5-(4-(2-(5-methyl-2-(2-thienyl)oxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine-2,4-dione);    -   (30) BM 131258        (5-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzothien-7-ylmethyl)thiazolidine-2,4-dione);    -   (31) CRE 16336 (EML 16336);    -   (32) HQL 975        (3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2        (S)-(propylamino)propionic acid);    -   (33) DRF 2189 (5-((4-(2-(1-Indolyl)ethoxy)phenyl)methyl)        thiazolidine-2,4-dione);    -   (34) DRF 554158;    -   (35) DRF-NPCC;    -   (36) CLX 0100, CLX 0101, CLX 0900, or CLX 0901;    -   (37) IkappaB Kinase (IKK B) Inhibitors    -   (38) mitogen-activated protein kinase (MAPK) inhibitors p38 MAPK        Stimulators    -   (39) phosphatidyl-inositide triphosphate    -   (40) insulin recycling receptor inhibitors    -   (41) glucose transporter 4 modulators    -   (42) TNF-α antagonists    -   (43) plasma cell differentiation antigen-1 (PC-1) Antagonists    -   (44) adipocyte lipid-binding protein (ALBP/aP2) inhibitors    -   (45) phosphoglycans    -   (46) Galparan;    -   (47) Receptron;    -   (48) islet cell maturation factor;    -   (49) insulin potentiating factor (IPF or insulin potentiating        factor-1);    -   (50) somatomedin C coupled with binding protein (also known as        IGF-BP3, IGF-BP3, SomatoKine);    -   (51) Diab II (known as V-411) or Glucanin, produced by Biotech        Holdings Ltd. or Volque Pharmaceutical;    -   (52) glucose-6 phosphatase inhibitors;    -   (53) fatty acid glucose transport protein;    -   (54) glucocorticoid receptor antagonists; and    -   (55) glutamine:fructose-6-phosphate amidotransferase (GFAT)        modulators.

(C) Biguanides, which decrease liver glucose production and increasesthe uptake of glucose. Examples include metformin such as:

-   -   (1) 1,1-dimethylbiguanide (e.g., Metformin-DepoMed,        Metformin-Biovail Corporation, or METFORMIN GR (metformin        gastric retention polymer)); and    -   (2) metformin hydrochloride (N,N-dimethylimidodicarbonimidic        diamide monohydrochloride, also known as LA 6023, BMS 207150,        GLUCOPHAGE, or GLUCOPHAGE XR.

(D) Alpha-glucosidase inhibitors, which inhibit alpha-glucosidase.Alpha-glucosidase converts fructose to glucose, thereby delaying thedigestion of carbohydrates. The undigested carbohydrates aresubsequently broken down in the gut, reducing the post-prandial glucosepeak. Examples include, but are not limited to:

-   -   (1) acarbose (D-glucose,        O-4,6-dideoxy-4-(((1S-(1alpha,4alpha,5beta,6alpha))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl)amino)-alpha-D-glucopyranosyl-(1-4)-—O—        alpha-D-glucopyranosyl-(1-4)-, also known as AG-5421, Bay-g-542,        BAY-g-542, GLUCOBAY, PRECOSE, GLUCOR, PRANDASE, GLUMIDA, or        ASCAROSE);    -   (2) Miglitol (3,4,5-piperidinetriol,        1-(2-hydroxyethyl)-2-(hydroxymethyl)-, (2R        (2alpha,3beta,4alpha,5beta))- or        (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl-3,4,5-piperidinetriol,        also known as BAY 1099, BAY M 1099, BAY-m-1099, BAYGLITOL,        DIASTABOL, GLYSET, MIGLIBAY, MITOLBAY, PLUMAROL);    -   (3) CKD-711        (0-4-deoxy-4-((2,3-epoxy-3-hydroxymethyl-4,5,6-trihydroxycyclohexane-1-yl)amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose);    -   (4) emiglitate        (4-(2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1-piperidinyl)ethoxy)benzoic        acid ethyl ester, also known as BAY o 1248 or MKC 542);    -   (5) MOR 14 (3,4,5-piperidinetriol, 2-(hydroxymethyl)-1-methyl-,        (2R-(2alpha,3beta,4alpha,5beta))-, also known as        N-methyldeoxynojirimycin or N-methylmoranoline); and    -   (6) Voglibose        (3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2—C-(hydroxymethyl)-D-epi-inositol        or        D-epi-Inositol,3,4-dideoxy-4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2—C-(hydroxymethyl)-,        also known as A 71100, AO 128, BASEN, GLUSTAT, VOGLISTAT.

(E) Insulins include regular or short-acting, intermediate-acting, andlong-acting insulins, non-injectable or inhaled insulin, tissueselective insulin, glucophosphokinin (D-chiroinositol), insulinanalogues such as insulin molecules with minor differences in thenatural amino acid sequence and small molecule mimics of insulin(insulin mimetics), and endosome modulators. Examples include, but arenot limited to:

-   -   (1) Biota;    -   (2) LP 100;    -   (3) (SP-5-21)-oxobis(1-pyrrolidinecarbodithioato—S, S′)vanadium,    -   (4) insulin aspart (human insulin (28B-L-aspartic acid) or        B28-Asp-insulin, also known as insulin X14, INA-X14, NOVORAPID,        NOVOMIX, or NOVOLOG);    -   (5) insulin detemir (Human        29B—(N-6-(1-oxotetradecyl)-L-lysine)-(1A-21A), (1B-29B)—Insulin        or NN 304);    -   (6) insulin lispro (“28B-L-lysine-29B-L-proline human insulin,        or Lys(B28), Pro(B29) human insulin analog, also known as        lys-pro insulin, LY 275585, HUMALOG, HUMALOG MIX 75/25, or        HUMALOG MIX 50/50);    -   (7) insulin glargine (human (A21-glycine, B31-arginine,        B32-arginine) insulin HOE 901, also known as LANTUS, OPTISULIN);    -   (8) Insulin Zinc Suspension, extended (Ultralente), also known        as HUMULIN U or ULTRALENTE;    -   (9) Insulin Zinc suspension (Lente), a 70% crystalline and 30%        amorphous insulin suspension, also known as LENTE ILETIN II,        HUMULIN L, or NOVOLIN L;    -   (10) HUMULIN 50/50 (50% isophane insulin and 50% insulin        injection);    -   (11) HUMULIN 70/30 (70% isophane insulin NPH and 30% insulin        injection), also known as NOVOLIN 70/30, NOVOLIN 70/30 PenFill,        NOVOLIN 70/30 Prefilled;    -   (12) insulin isophane suspension such as NPH ILETIN II, NOVOLIN        N, NOVOLIN N PenFill, NOVOLIN N Prefilled, HUMULIN N;    -   (13) regular insulin injection such as ILETIN II Regular,        NOVOLIN R, VELOSULIN BR, NOVOLIN R PenFill, NOVOLIN R Prefilled,        HUMULIN R, or Regular U-500 (Concentrated);    -   (14) ARIAD;    -   (15) LY 197535;    -   (16) L-783281; and    -   (17) TE-17411.

(F) Insulin secretion modulators such as:

-   -   (1) glucagon-like peptide-1 (GLP-1) and its mimetics;    -   (2) glucose-insulinotropic peptide (GIP) and its mimetics;    -   (3) exendin and its mimetics;    -   (4) dipeptyl protease (DPP or DPPIV) inhibitors such as        -   (4a) DPP-728 or LAF 237            (2-pyrrolidinecarbonitrile,1-(((2-((5-cyano-2-pyridinyl)amino)ethyl)amino)acetyl),            known as NVP-DPP-728, DPP-728A, LAF-237);        -   (4b) P 3298 or P32/98            (di-(3N-((2S,3S)-2-amino-3-methyl-pentanoyl)-1,3-thiazolidine)fumarate);        -   (4c) TSL 225            (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic            acid);        -   (4d) Valine pyrrolidide (valpyr);        -   (4e) 1-aminoalkylisoquinolinone-4-carboxylates and analogues            thereof;        -   (4f) SDZ 272-070 (1-(L-Valyl)pyrrolidine);        -   (4g) TMC-2A, TMC-2B, or TMC-2C;        -   (4h) Dipeptide nitriles (2-cyanopyrrolodides);        -   (41) CD26 inhibitors; and        -   (4j) SDZ 274-444;    -   (5) glucagon antagonists such as AY-279955; and    -   (6) amylin agonists which include, but are not limited to,        pramlintide (AC-137, Symlin, tripro-amylin or pramlintide        acetate).

The present compounds may also increase insulin sensitivity with littleor no increase in body weight than that found with the use of existingPPAR gamma agonists. Oral anti-diabetic agents may include insulin,sulfonylureas, biguanides, meglitinides, AGI's, PPAR alpha agonists, andPPAR gamma agonists, and dual PPAR alpha/gamma agonists.

The present compounds also may increase fat and/or lipid metabolism,providing a method for losing weight, losing fat weight, lowering bodymass index, lowering lipids (such as lowering triglycerides), ortreating obesity or the condition of being overweight. Examples of lipidlowering agents include bile acid sequestrants, fibric acid derivatives,nicotinic acid, and HMGCoA reductase inhibitors. Specific examplesinclude statins such as LIPITOR®, ZOCOR®, PRAVACHOL®, LESCOL®, andMEVACOR®, and pitavastatin (nisvastatin) (Nissan, Kowa Kogyo, Sankyo,Novartis) and extended release forms thereof, such as ADX-159 (extendedrelease lovastatin), as well as Colestid, Locholest, Questran, Atromid,Lopid, and Tricor.

Examples of blood pressure lowering agents include anti-hypertensiveagents, such as angiotensin-converting enzyme (ACE) inhibitors(Accupril, Altace, Captopril, Lotensin Mavik, Monopril, Prinivil,Univasc, Vasotec, and Zestril), adrenergic blockers (such as Cardura,Dibenzyline, Hylorel, Hytrin, Minipress, and Minizide) alpha/betaadrenergic blockers (such as Coreg, Normodyne, and Trandate), calciumchannel blockers (such as Adalat, Calan, Cardene, Cardizem, Covera-HS,Dilacor, DynaCirc, Isoptin, Nimotop, Norvace, Plendil, Procardia,Procardia XL, Sula, Tiazac, Vascor, and Verelan), diuretics, angiotensinII receptor antagonists (such as Atacand, Avapro, Cozaar, and Diovan),beta adrenergic blockers (such as Betapace, Blocadren, Brevibloc,Cartrol, Inderal, Kerlone, Lavatol, Lopressor, Sectral, Tenormin,Toprol-XL, and Zebeta), vasodilators (such as Deponit, Dilatrate, SR,Imdur, Ismo, Isordil, Isordil Titradose, Monoket, Nitro-Bid, Nitro-Dur,Nitrolingual Spray, Nitrostat, and Sorbitrate), and combinations thereof(such as Lexxel, Lotrel, Tarka, Teczem, Lotensin HCT, Prinzide,Uniretic, Vaseretic, Zestoretic).

F. Biological Examples

Transfection Assay Method for PPAR Receptors

HEK293 cells were grown in DMEM/F12 medium supplemented with 10% FBS andglutamine (Invitrogen) and incubated in a 5% CO₂ incubator at 37° C. Thecells were co-transfected using DMRIE-C reagent (Invitrogen) in serumfree medium (Opti-MEM, Invitrogen) with two mammalian expressionplasmids, one containing the DNA sequence coding for the ligand bindingdomains of either PPARα, γ or 6 fused to the yeast GAL4 DNA bindingdomain and the other containing the promoter sequence of the yeast GAL4(UAS) fused to the firefly luciferase cDNA reporter. The next day, themedium was changed to DMEM/F12 medium supplemented with 5% charcoaltreated serum (Hyclone) and glutamine. After 6 hrs the cells weretrypsinized and seeded at a density of 50,000 cells/well into 96 wellplates and incubated overnight as above. The cells were then treatedwith test compounds or vehicle and incubated for 18-24 hrs as above.Luciferase reporter activity was measured using the Steady-GloLuciferase Assay Kit from Promega. DMRIE-C Reagent was purchased fromGIBCO Cat. No. 10459-014. OPTI-MEM I Reduced Serum Medium was purchasedfrom GIBCO (Cat. No. 31985). Steady-Glo Luciferase Assay Kit waspurchased from Promega (Part# E254B).

A variety of example compounds have been made and tested, with a rangeof in vitro results. Below are representative compounds and data; insome cases, where multiple EC₅₀'s are shown, multiple measurements weretaken. Naturally, different compounds in Formula (I) may have not haveactivities identical to any one compound below.

TABLE 2 In Vitro Data Compound EC₅₀ (PPAR delta) EC₅₀ (PPAR EC₅₀ (PPARalpha) Number nM gamma) nM nM 2 41.5 899 900

G. Other Embodiments

The features and principles of the invention are illustrated in thediscussion, examples, and claims herein. Various adaptations andmodifications of the invention will be apparent to a person of ordinaryskill in the art and such other embodiments are also within the scope ofthe invention. Publications cited herein are incorporated in theirentirety by reference.

1. A method of treating a condition selected from the group consistingof diabetes, cardiovascular disease, Metabolic X Syndrome,hypercholesterolemia, hypo-HDL-cholesterolemia,hyper-LDL-cholesterolemia, dyslipiedmia, atherosclerosis, obesity, andcomplications thereof, said method comprising administering to a patientin need thereof a jointly effective amount of (a) a compound of formula(I):

wherein X is selected from a covalent bond, S, and O; Y is S or O; Z isO or CH₂, provided when Y is O, then Z is O; R₁ and R₂ are independentlyselected from H, C₁₋₃ alkyl, C₁₋₃ alkoxy, halo, and NR_(a)R_(b) whereinR_(a) and R_(b) are independently H or C₁₋₃ alkyl; R₃ and R₄ areindependently selected from H, halo, cyano, C₁₋₅ alkyl, hydroxy,C₂₋₄acyl, C₁₋₄ alkoxy, and NR_(c)R_(d) wherein R_(c) and R_(d) areindependently H or C₁₋₃ alkyl, provided that R₃ and R₄ are not both H;R₅ and R₆ are independently selected from H, C₁₋₈ alkyl and substitutedC₁₋₈ alkyl, provided that R₅ and R₆ are not both H; R₇ is selected fromH, halo, C₁₋₈ alkyl, and phenyl; R₈ and R₉ are independently selectedfrom halo, phenyl, C₁₋₉ alkyl, C₁₋₈ alkoxy, C₂₋₉ alkenyl, C₂₋₉alkenyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy, C₃₋₇cycloalkyl-C₁₋₇alkyl,C₃₋₇cycloalkyl-C₁₋₇alkoxy, C₃₋₇cycloalkyloxy-C₁₋₆alkyl, andC₃₋₇cycloalkyloxy-C₁₋₇alkoxy, or R₈ and R₉ together form C₁₋₉alkylidenylor C₃₋₉ alkenylidenyl; or R₈, R₉ and the carbon atom to which they areattached together form C₃₋₇ cycloalkyl or 5- or 6-membered heterocyclyl;n is 0, 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptablesalt thereof; and (b) a second pharmaceutical agent selected from thegroup consisting of an oral antidiabetic agent, a lipid lowering agent,and a blood pressure lowering agent.
 2. The method of claim 1 whereinthe second pharmaceutical agent is an oral antidiabetic agent selectedfrom the group consisting of insulin, a sulfonylurea, a biguanide, ameglitinide, an AGI, a PPAR alpha agonist, a PPAR gamma agonist, a dualPPAR alpha/gamma agonist.
 3. The method of claim 1 wherein the secondpharmaceutical agent is a lipid lowering agent selected from the groupconsisting of an acid sequestrant, a fibric acid derivative, a nicotinicacid, and HMGCoA reductase inhibitor.
 4. The method of claim 1 whereinthe second pharmaceutical agent is a blood pressure lowering agentselected from the group consisting of an angiotensin-converting enzyme(ACE) inhibitor, an adrenergic blocker, an alpha/beta adrenergicblocker, a calcium channel blocker, a diuretic, an angiotensin IIreceptor antagonist, a beta adrenergic blocker, a vasodilator, andcombinations thereof.
 5. The method of claim 1 wherein the wherein X isS or O for the compound of formula (I).
 6. The method of claim 1 whereinX is O for the compound of formula (I).
 7. The method of claim 1 whereinY is O for the compound of formula (I).
 8. The method of claim 1 whereinY is S for the compound of formula (I).
 9. The method of claim 1 whereinZ is O for the compound of formula (I).
 10. The method of claim 1wherein Z is CH₂ for the compound of formula (I).
 11. A pharmaceuticalcomposition comprising a jointly effective amount of (a) a compound offormula (I):

wherein X is selected from a covalent bond, S, and O; Y is S or O; Z isO or CH₂, provided when Y is O, then Z is O; R₁ and R₂ are independentlyselected from H, C₁₋₃ alkyl, C₁₋₃ alkoxy, halo, and NR_(a)R_(b) whereinR_(a) and R_(b) are independently H or C₁₋₃ alkyl; R₃ and R₄ areindependently selected from H, halo, cyano, C₁₋₅ alkyl, hydroxy,C₂-₄acyl, C₁-₄ alkoxy, and NR_(c)R_(d) wherein R_(c) and R_(d) areindependently H or C₁₋₃ alkyl, provided that R₃ and R₄ are not both H;R₅ and R₆ are independently selected from H, C₁₋₈ alkyl and substitutedC₁₋₈ alkyl, provided that R₅ and R₆ are not both H; R₇ is selected fromH, halo, C₁₋₈ alkyl, and phenyl; R₈ and R₉ are independently selectedfrom halo, phenyl, C₁₋₉ alkyl, C₁₋₈ alkoxy, C₂₋₉ alkenyl, C₂₋₉alkenyloxy, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy, C₃₋₇cycloalkyl-C₁₋₇alkyl,C₃₋₇cycloalkyl-C₁₋₇alkoxy, C₃₋₇cycloalkyloxy-C₁₋₆alkyl, andC₃₋₇cycloalkyloxy-C₁₋₇alkoxy, or R₈ and R₉ together form C₁₋₉alkylidenylor C₃₋₉ alkenylidenyl; or R₈, R₉ and the carbon atom to which they areattached together form C₃₋₇ cycloalkyl or 5- or 6-membered heterocyclyl;n is 0, 1 or 2; and m is 0, 1 or 2; or a pharmaceutically acceptablesalt thereof; and (b) a second pharmaceutical agent selected from thegroup consisting of an oral antidiabetic agent, a lipid lowering agent,and a blood pressure lowering agent; and a pharmaceutically acceptablecarrier.
 12. The pharmaceutical composition of claim 11 wherein thesecond pharmaceutical agent is an oral antidiabetic agent selected fromthe group consisting of insulin, a sulfonylurea, a biguanide, ameglitinide, an AGI, a PPAR alpha agonist, a PPAR gamma agonist, a dualPPAR alpha/gamma agonist.
 13. The pharmaceutical composition of claim 11wherein the second pharmaceutical agent is a lipid lowering agentselected from the group consisting of an acid sequestrant, a fibric acidderivative, a nicotinic acid, and HMGCoA reductase inhibitor.
 14. Thepharmaceutical composition of claim 11 wherein the second pharmaceuticalagent is a blood pressure lowering agent selected from the groupconsisting of an angiotensin-converting enzyme (ACE) inhibitor, anadrenergic blocker, an alpha/beta adrenergic blocker, a calcium channelblockers, a diuretic, an angiotensin II receptor antagonist, a betaadrenergic blocker, a vasodilator, and combinations thereof.
 15. Thepharmaceutical composition of claim 11 wherein X is S or O for thecompound of formula (I).
 16. The pharmaceutical composition of claim 11wherein X is O for the compound of formula (I).
 17. The pharmaceuticalcomposition of claim 11 wherein Y is O for the compound of formula (I).18. The pharmaceutical composition of claim 11 wherein Y is S for thecompound of formula (I).
 19. The pharmaceutical composition of claim 11wherein Z is O for the compound of formula (I).
 20. The pharmaceuticalcomposition of claim 11 wherein Z is CH₂ for the compound of formula(I).